Revised Abstract: "Pathology Core", will provide the program project investigators with expert pathological evaluation of all bladder cancer specimens that present at USC/Norris Comprehensive Cancer Center, as well as collaborate with the Tumor Procurement Service. Although the core was considered an excellent service for acquisition and validation of samples, there was concern in the previous review that more oversight of the immunohistochemical staining and interpretation could be provided. The previous review raised questions with regard to the apparent lack of expert quality control in the projects as opposed to the core. Having Dr. Hawes' take a more active role in the interpretation of the immunohistochemical findings in the projects, rather than limiting her activity to validation studies and antibody quality control has answered this concern. In addition, the applicants have now provided a detailed description of quality control including double reading of five percent of cases by both individuals responsible for the immunohistochemical interpretation in Project 2 (Dr. Hawes and Dr. Shi), a plan for arbitrating disparate results and a five percent restaining protocol. This core was previously rated as satisfactory and is now rated as superior. In summary, this highly meritorious program project is exciting and timely. It is becoming clear, largely through the work of the Principal Investigator, that an increasing number of genes with important biological functions in growth regulation, DNA repair, and apoptosis are silenced via DNA methylation in CpG islands located in promoter sequences. It will be critical to determine the qualitative and quantitative nature of these changes, the timing of de novo methylation, and the biological significance of these DNA modifications in tumor progression. Advancements on this front would be a major conceptual leap and could potentially provide novel targets for clinical intervention. The Principal Investigator and his colleagues remain at the forefront of research into the biology of the initiation and progression of bladder cancer and it is anticipated that they will continue to contribute to this important area. The program investigators represent a unique, innovative and well-organized interaction of epidemiologists, molecular biologists and pathologists in a highly significant translational research project. The investigators have an excellent history of collaboration and have planned a highly integrated program involving three projects and three enabling cores. The translational nature of their collaborations to date has been superb as is the research environment with the USC Norris Comprehensive Cancer Center and the Genitourological Group pioneered by Dr. Donald Skinner. The program is supported by the availability of excellent tissue resources associated with epidemiologic and outcome databases. Given the combined expertise of the investigators and their appropriate response to the previous review, the program has been strengthened even more since the previous review and has a high likelihood of being successful and with a high probability that significant new basic and translational knowledge in the field of bladder cancer will be generated. Support is enthusiastically recommended for five years.